RNA-seq analysis in fibroblast IMR90 CTRL/MYC/MYC+SF3A3 KD
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ABSTRACT:
PROVIDER: PRJNA615007 | ENA |
REPOSITORIES: ENA
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Project description:Splicing is a central RNA-based process commonly altered in human cancers; however, how the splicing machinery is co-opted during tumorigenesis remains largely unresolved. Here we identify the splice factor SF3A3 at the nexus of an oncogenic translation program that rewires splicing to promote tumorigenesis. Our results suggest that key spliceosomal networks centered on the essential core U2-associated factor, SF3A3, are exquisitely controlled at the translation level during oncogenic stress. Upon oncogene activation, SF3A3 translation is rapidly enabled via a conserved internal stem-loop structure embedded in the transcript 5’ untranslated region (UTR). Uncoupled SF3A3 translation leads to alternative splicing of several mRNAs involved in mitochondrial dynamics, and induces a metabolic switch that fuels cancer initiation properties in MYC-driven breast tumorigenesis in vivo. Finally, we compelling show that SF3A3 is post-transcriptionally altered and predicts for poor prognosis in aggressive triple negative breast cancers. Together, these findings unveil a highly dynamic regulatory network that interfaces mRNA splicing and translation to orchestrate cancer gene expression networks.
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Project description:SF3B1 is the most mutated splicing factor (SF) in myelodysplastic syndromes (MDS), clonal hematopoietic disorders with variable risk of leukemic transformation. Although the tumorigenic effects of SF3B1 mutations have been defined, the role of “non-mutated” SF3B1 in cancer remains largely unresolved. Here we identify a conserved epitranscriptomic program that steers SF3B1 translation to counteract leukemogenesis. Our analysis of human and murine pre-leukemic MDS cells reveals a remarkable SF3B1 protein increase. Selective inhibition of SF3B1 upregulation accelerates MDS-to-leukemia progression in vivo. Mechanistically, ALKBH5-driven m6A demethylation within the SF3B1 5’ UTR fine-tunes SF3B1 translation to direct splicing of central DNA repair and epigenetic regulators during transformation. Loss of 5’ UTR m6A increases SF3B1 abundance, genome stability and delays leukemia progression in vivo, supporting integrative analysis of SF3B1 molecular signatures in humans that may predict tumor mutational burden and poor prognosis. These findings highlight a post-transcriptional gene expression nexus that unveils unanticipated SF3B1-dependent cancer vulnerabilities.
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Project description:Mammalian SIRT1 is a central regulator of metabolism and aging. This project is to analyze global phosphorylation levels of mammalian SIRT1 in proliferating and senescence states using human lung fibroblast IMR90, in order to explore the post-translational regulation of SIRT1 protein upon cellular senescence and its potential roles in the regulatory mechanisms of SIRT1 homeostasis.
2020-09-29 | PXD020081 | Pride
Project description:We produced a map of nucleosome positions in IMR90 by sequencing the ends of MNase-digested chromatin fragments.
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Project description:To understand how KD regulates gene expression, the gene expression profiles of livers from mice fed a control (Ctrl) or KD are compared using RNA-seq
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Project description:We produced a map of nucleosome positions in IMR90 by sequencing the ends of MNase-digested chromatin fragments. IMR90 cells were grown in culture, about 1E6 cells were isolated and digested using micrococcal nuclease (MNase). Mononucleosomes were gel-selected and fragment ends were sequenced using the Illumina GAIIx sequencing platform.
2011-04-01 | E-GEOD-21823 | biostudies-arrayexpress
Project description:Micrococcal nuclease (Mnase) treatment and sequencing of mononucleosomal DNA One single sample in the IMR90 fibroblast cell line
2015-03-03 | E-GEOD-44985 | biostudies-arrayexpress
Project description:Gene expression data from IMR90 Control, IMR90 HRAS-G12V, IMR90 HRAS-G12V+shDOT1L, IMR90 DOT1L Overexpression
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Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are to analysis the differiational genes and pathways in Ctrl-siRNA and c-Myc-siRNA lymphoma cells by using NGS-derived lymphoma transcriptome profiling (RNA-seq). Methods: Ctrl-siRNA and c-Myc-siRNA cells' mRNA profiles were generated by deep sequencing, in triplicate, using Illumina HiSeq 4000. The sequence reads that passed quality filters were analyzed at the transcript isoform level with following methods: Alignment by using HISAT2 v2.1, IGV was used to to view the mapping result by the Heatmap, histogram, scatter plot or other stytle, FPKM was then calculated to estimate the expression level of genes in each sample, DEGseq v1.18.0 was used for differential gene expression analysis between two samples with non biological replicates and Function Enrichment Analysis including GO enrichment analysis and KEGG . Conclusions: Our study represents the first detailed analysis of Ctrl-siRNA and c-Myc-siRNA cells' transcriptomes, with biologic replicates, generated by RNA-seq technology. The optimized data analysis workflows reported here should provide a framework for comparative investigations of expression profiles. Our results show that NGS offers a comprehensive and more accurate quantitative and qualitative evaluation of mRNA content within a cell or tissue. We conclude that RNA-seq based transcriptome characterization would expedite genetic network analyses and permit the dissection of complex biologic functions.
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2013-11-12 | E-GEOD-44303 | biostudies-arrayexpress